The long-term objective of these studies is to clarify factors that regulate blood flow to the brain under normal conditions and in disease states. We plan to examine three concepts that have emerged recently. First, there are major differences in regulation of blood flow to the brain stem and cerebrum. Second, central neural pathways, as well as peripheral pathways, may affect cerebral vessels. Third, cerebral veins are the primary site of disruption of the blood-brain barrier. Studies are planned in relation to each of these concepts. First, we propose to use a new method that we have developed to determine resistance of large arteries to the brain stem. Responses of large arteries to sympathetic stimulation and humoral stimuli will be examined. We also propose to examine physiological determinants and consequences of pronounced rhythmic contractions of the basilar artery, which we have observed in vivo. Studies also are planned to determine whether increases in blood flow through the basilar artery, at constant pressure, produce flow-dependent endothelium-mediated vasodilatation. Second, we propose to examine effects of neural stimuli on cerebral vessels. We plan to determine whether the protective effect of sympathetic nerves during acute hypertension is mediated by attenuation of increases in cerebral venous pressure. Studies also are proposed to examine the role of central neural pathways in regulation of cerebral blood flow. We plan to determine whether electrical and chemical stimulation of the fastigial nucleus produce direct cerebral vasodilatation, which is not secondary to increased cerebral metabolism. Chemical stimulation will avoid excitation of axons that pass through the region. Third, we plan to pursue the finding that cerebral venules, not arterioles or capillaries, are the primary site of disruption of the blood-brain barrier. We propose to determine whether molecular charge affects the site of disruption of the barrier. Studies are proposed to examine mechanisms by which chronic hypertension alters susceptibility to disruption of the blood-brain barrier. Studies also are planned to determine whether acidosis and vasodilatation separately affect susceptibility of the blood-brain barrier to disruption.